Clinical Trials Register

Summary
EudraCT Number:	2017-000110-35
Sponsor's Protocol Code Number:	V501-046
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-01-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2017-000110-35

A.3

Full title of the trial

Evaluation of Safety and Immunogenicity of GARDASIL™ in Healthy Females Between 9 and 26 Years of Age in SubSaharan Africa.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

GARDASIL™ Study in Healthy Females Between 9 and 26 Years of Age in Sub-Saharan Africa

A.3.2

Name or abbreviated title of the trial where available

Safety and Immunogenicity of GARDASIL™ in Healthy Females Between 9 and 26 Years of Age

A.4.1

Sponsor's protocol code number

V501-046

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01245764

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck & Co., Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck & Co., Inc.
B.5.2	Functional name of contact point	Rituparna Das
B.5.3	Address:
B.5.3.1	Street Address	One Merck Drive - P.O. Box 100
B.5.3.2	Town/ city	Whitehouse Station, NJ
B.5.3.3	Post code	08889-0100
B.5.3.4	Country	United States
B.5.4	Telephone number	+1267-305-0416
B.5.5	Fax number	+1267-305-5970
B.5.6	E-mail	Rituparna.das@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	GARDASIL
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Pasteur MSD SNC
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Quadrivalent Human Papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine
D.3.2	Product code	V501
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Papillomavirus Type 6 L1 protein
D.3.9.3	Other descriptive name	HPV 6 TYPE L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.4	EV Substance Code	SUB25327
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Papillomavirus Type 11 L1 protein
D.3.9.3	Other descriptive name	HPV TYPE 11 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.4	EV Substance Code	SUB25330
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Papillomavirus Type 16 L1 protein
D.3.9.3	Other descriptive name	HPV TYPE 16 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.4	EV Substance Code	SUB25329
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Papillomavirus Type 18 L1 protein
D.3.9.3	Other descriptive name	HPV TYPE 18 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.4	EV Substance Code	SUB25328
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Suspension for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Vaccination against HPV infection/related disease

E.1.1.1

Medical condition in easily understood language

Vaccination against HPV infection/related disease

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10071147
E.1.2	Term	Human papilloma virus immunization
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase A-Primary Phase
Immunogenicity: To estimate the percentage of subjects who seroconvert to each of HPV 6, 11, 16, and 18 at Month 7 (4 weeks Postdose 3).
Safety: To evaluate the safety and tolerability of GARDASIL in females 9- 26 years of age in SubSaharan Africa.

Phase B-Vaccination of Placebo Subjects
A summary of the serious adverse experiences that occur during this phase of the study will be provided.

E.2.2

Secondary objectives of the trial

Immunogenicity: To estimate Month 7 anti-HPV 6, 11, 16, and 18 geometric mean titers (GMTs) in vaccinated subjects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Phase A-Primary Phase
1. Healthy female subjects aged 9 to 26 years old who are native to and living in a participating SubSaharan African country.
2. Subject agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes. If a potential subject does not have a telephone number, the subject must provide an address at which he or she may be contacted.
3. For post-pubertal female subjects, no evidence of current pregnancy, as demonstrated by a negative urine -hCG test.
4. For subjects who are sexually active, must agree to use effective contraception or remain abstinent through Month 7 of the study. Effective contraception will be considered to include oral birth control pills or at least single-barrier contraception (males using condom or females using diaphragm, contraceptive sponge, or IUD and etc.)
5. For subjects who have not yet had sexual intercourse, must either agree to remain abstinent through Month 7 of the study, or if they become sexually active during the vaccination phase of the study, to use effective contraception through Month 7. Effective contraception will be considered to include oral birth control pills or at least single-barrier contraception (males using condom or females using diaphragm, contraceptive sponge, or IUD and etc.)
6. Subject is judged to be in good physical health on the basis of medical history, physical examination and laboratory testing.
7. Subjects who have had sexual intercourse in the two weeks prior to enrollment must have been using effective contraception as defined above. (Emergency contraception is not considered effective contraception for enrollment in the study.)

Phase B-Vaccination of Placebo Subjects
To be eligible to receive vaccination with GARDASIL in this phase of the study, subjects must have received placebo during the Primary Phase of the study. In addition, subjects must meet inclusion criteria 4-7 above.

E.4

Principal exclusion criteria

Phase A-Primary Phase
1. Subject is pregnant as determined by a positive urine -hCG test.
2. Subject has had a temperature ≥37.8ºC or ≥100ºF (oral or oral equivalent) within 24 hours prior to the first injection.
3. Subject is currently enrolled in another clinical study of an investigational agent or agents.
4. Subject has a history of known prior vaccination with a HPV vaccine, or was previously enrolled in an HPV vaccine study and received either active agent or placebo.
5. Subject has received any inactivated vaccine within 14 days prior to enrollment or any live vaccine within 21 days prior to enrollment.
6. Subject has a history of severe allergic reaction to any agent (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention.
7. Subject has known allergy to any vaccine component, including aluminum, yeast or BENZONASE (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]).
8. Subject has received any immune globulin preparation or blood-derived products within the 6 months prior to the first injection, or plans to receive any such products during the course of the study.
9. Subject has a history of splenectomy, known autoimmune disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis), or is receiving immunosuppressives (e.g., substances or treatments known to diminish immune response such as radiation therapy, administration of antimetabolites, antilymphocytic sera, systemic corticosteroids). Individuals who have received periodic treatments with immunosuppressives, defined as at least 3 courses of systemic corticosteroids each lasting at least 1 week in duration for the year prior to enrollment, will be excluded. Subjects using topical steroids (i.e., inhaled or nasal) will be eligible for vaccination.
10. Subject is immunocompromised or has been diagnosed as having HIV infection (either through prior diagnosis or by the rapid HIV test at study screening).
11. Subject has known thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections.
12. Subject has known sickle cell anemia disease (sickle cell trait is not an exclusion), active malaria or active tuberculosis.
13. Subject has any condition which in the opinion of the investigator might interfere with the evaluation of the study objectives.
14. Subject has a history of recent or ongoing alcohol or other drug abuse.
15. Subject is unable to give consent/assent.
16. Subject has a prior history of an abnormal Pap test showing squamous intraepithelial lesion (SIL) or ASC-US, ASC-H, or biopsy showing cervical intraepithelial neoplasia (CIN) or worse.
17. Subject has any prior history (or at Day 1) of genital warts or treatment for genital warts.
18. Subject has >4 lifetime sexual partners.
19. Subject has undergone hysterectomy with removal of the cervix.
20. Subject plans to permanently relocate from the area prior to the completion of the study or to leave for an extended period of time when study visits would need to be scheduled.

Phase B-Vaccination of Placebo Subjects
Subjects must not have had a temperature ≥37.8ºC or ≥100ºF (oral or oral equivalent) within the 24 hours prior to the first injection.

E.5 End points

E.5.1

Primary end point(s)

Primary Immunogenicity Endpoint (Phase A only)
Percentage of subjects who seroconvert to each of HPV 6, 11, 16, 18 at Month 7. A subject is defined to have seroconverted to HPV types 6, 11, 16, and 18 if the subject has HPV 6, 11, 16, and 18 titers less than 20, 16, 20, and 24 mMU/mL, respectively, at Day 1; and greater than or equal to 20, 16, 20, and 24 mMU/mL, respectively, at Month 7 (1 month post dose 3 of GARDASIL™).

Safety Endpoints
The main outcomes for safety/ tolerability are: (1) VRC-prompted injection-site adverse experiences (pain, swelling and redness), and temperature elevations (oral temperature ≥37.8°C [≥100°F]) on days 1-5 following any vaccination visit; (2) serious adverse experiences at any time during the study.

E.5.1.1

Timepoint(s) of evaluation of this end point

All subjects were followed to assess safety and immunogenicity through Month 7. Phase A subjects were followed for serious clinical adverse experiences, pregnancy and outcome of pregnancy (including health of the infant) from Month 7 through Month 12 of Phase A. Subjects vaccinated in Phase B of the study and were ollowed for serious clinical adverse experiences, pregnancy and outcome of pregnancy (including health of the infant).

E.5.2

Secondary end point(s)

Secondary Immunogenicity Endpoint (Phase A only)
Serum geometric mean titers (GMTs) to each of HPV 6, 11, 16, 18 at Month 7.

Safety endpoints
The main outcomes for safety/ tolerability are: (1) VRC-prompted injection-site adverse experiences (pain, swelling and redness), and temperature elevations (oral temperature ≥37.8°C [≥100°F]) on days 1-5 following any vaccination visit; (2) serious adverse experiences at any time during the study.

E.5.2.1

Timepoint(s) of evaluation of this end point

All subjects were followed to assess safety and immunogenicity through Month 7

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Phase B Open

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Ghana

Kenya

Senegal

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

150

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

250

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Senegal

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